Project Summary/Abstract The overall goal of the Sanderson Lab is to determine the role of the heparan sulfate / heparanase axis in regulating cancer and to use this knowledge to develop new anti-cancer therapies. The immediate goal of this project is to define heparanase regulation of the metastatic cascade using multiple myeloma as a model cancer. Myeloma is a devastating cancer that thrives in the bone marrow and disseminates throughout the skeleton leading to severe pain, poor quality of life and eventual death of the patient. Although it is the metastatic nature of this cancer that kills patients, unfortunately, the mechanisms regulating metastasis in myeloma are unknown. The key to improving patient treatment lies in developing a mechanistic understanding of myeloma metastasis and testing new inhibitors to block tumor dissemination. Using in vivo models, we have shown that the heparan sulfate degrading enzyme heparanase is a key driver of myeloma growth, angiogenesis, osteolysis and metastasis. Importantly, we also discovered that enzymatically active heparanase is present within the bone marrow of myeloma patients and it correlates with poor patient prognosis. Striking new data from our lab indicates that heparanase acts as a master regulator of metastasis in myeloma by upregulating expression of several genes including VEGF, MMP-9 and uPA/uPAR that work in concert to drive metastasis. We hypothesize that heparanase acts as a key mediator of myeloma metastasis by promoting initial intravasation of tumor cells into the blood at the primary tumor site and by preparing pre-metastatic niches in bone that facilitate tumor cell homing and growth. Given these two critical functions in metastasis, we further hypothesize that heparanase inhibitors in combination with other anti-myeloma compounds will provide a novel and potent therapeutic approach to this deadly disease. Aim 1 will examine the importance of heparanase in driving myeloma metastasis, the stage(s) of metastasis where heparanase exerts its effects and the influence of heparanase on establishing pre-metastatic niches in the bone marrow. Aim 2 will test a novel heparanase inhibitor in for its anti- metastatic effects in vivo when administered either as a single agent or in combination with dexamethasone.